Abstract

The syntheses of 3-[1-(4-sulfamoylphenyl)-5-p-tolyl-1H-pyra­zol-3-yl]propanoic acid, C19H19N3O4S, (I), and 3-[5-(4-bromo­phen­yl)-1-(4-sulfamoyl­phen­yl)-1H-pyrazol-3-yl]­propanoic acid–dichloro­methane–diethyl ether–water (2/0.72/1/1), 2C18H16BrN3O4S·0.72CH2Cl2·C4H10O·H2O, (II), are regio­specific. However, correct identification by spectroscopic techniques of the regioisomer formed is not trivial and single-crystal X-ray analysis provided the only means of unambiguous structure determination. Both structures make extensive use of hydrogen bonding and while compound (I) forms a straightforward unsolvated Z′ = 1 structure, compound (II) crystallizes as an unusual mixed solvate, with two crystallographically unique mol­ecules of the pyrazole derivative present in the asymmetric unit. The structure of (II) also features BrBr inter­actions.

Comment

Nonsteroidal anti-inflammatory drugs are divided into three different categories, namely classical cyclo­oxygenase-1 (COX1) inhibitors, cyclo­oxygenase-2 (COX2) inhibitors and dual inhibitors (Charlier & Michaux, 2003). In pharmaco­logical terms, they possess analgesic, anti-inflammatory and anti­pyretic effects (Charlier & Michaux, 2003; Antoniou et al., 2007). COX1 inhibitors were replaced by COX2 inhibitors due to problems of severe gastrointestinal irritation and renal impairment experienced by COX1 patients (Copeland et al., 1995). In the USA, only the COX2 inhibitor celecoxib is approved for the treatment of various forms of arthritis and even then the Food and Drug Administration requires a warning label highlighting the potential of an increased risk of cardiovascular events (Antoniou et al., 2007). This prompted us to synthesize celecoxib analogues and to investigate their pharmacological properties. In the process of synthesizing these analogues, we found that a mixture of regioisomers was possible, identified as 1 and 2 in the scheme below. Efforts to identify unambiguously the correct regioisomer by heteronuclear multiple-bond correlation (two-dimensional HMBC) and one-dimensional nuclear Overhauser effect (one-dimensional NOE) NMR spectroscopy were not successful, leaving single-crystal X-ray diffraction as the only possible means of unambiguous identification. We report here the structures of two related analogues, viz. the title compounds, (I) and (II).<!?show [softreturn]><!?show [softreturn]>

The asymmetric unit of (I) is shown in Fig. 1. The mol­ecular dimensions are unexceptional and the compound is unambiguously regioisomer 1. A mean plane fitted through the central pyrazole ring has an r.m.s. deviation of 0.0036 Å, showing it to be essentially planar. The benzene­sulfonamide ring is rotated by 28.73 (9)° from the plane of the pyrazole ring, while the tolyl ring is essentially planar (r.m.s. deviation of a plane fitted through all seven C atoms = 0.0137 Å) and is rotated by 70.26 (6)° from the plane of the pyrazole ring. The propanoic acid group has an extended structure but is not planar, with the C16—C17—C18—O4 torsion angle being −138.85 (16)°, and the r.m.s. deviation of a mean plane fitted through atoms C16, C17, C18, O3 and O4 is 0.2287 Å. This mean plane is rotated by 48.01 (8)° from the plane of the pyrazole ring.

Compound (II) crystallizes, unusually, with three separate and chemically different solvent mol­ecules (dichloro­methane, diethyl ether and water) present in the asymmetric unit, along with two mol­ecules of the pyrazole derivative itself (Fig. 3). Thus, Z′ = 1, since this represents the empirical chemical formula. In the following discussion, reference is made to the mol­ecule containing atoms Br1–C18 (mol­ecule A), with details for the mol­ecule containing atoms Br51–C68 (mol­ecule B) given in square brackets. Both mol­ecules A and B are unambiguously regioisomer 1.

The asymmetric unit of (II), showing the atom-numbering scheme. Displacement ellipsoids are drawn at the 50% probability level. C-bound H atoms have been omitted.

The presence of three separate solvent mol­ecules is rather unusual. Diethyl ether and dichloro­methane were used for recrystallization and the identity of the remaining solvent mol­ecule was established by analysis of difference Fourier maps, which clearly showed the water H atoms; they are also involved in hydrogen bonding, which is discussed below. The source of the water is probably due to using bench, rather than rigourously dried, solvents for recrystallization. The displacement ellipsoids for dichloro­methane are rather large, especially when compared with the remainder of the structure and considering that the data were measured at 115 K. In this case, free refinement of the dichloro­methane atom occupancies suggests that it is only ca 0.72 occupied, consistent with the observation that the crystals lost solvent when removed from the mother liquor. This model also yields lower refinement residuals than a fully ordered model. The presence of three different solvent mol­ecules is not without precedent. The Cambridge Structural Database (CSD, Version 5.30 plus two updates; Allen, 2002) has 21 examples of reported structures containing diethyl ether, dichloro­methane and water solvent mol­ecules, all of them metal complexes.

The mol­ecular dimensions of (II) are unexceptional. A mean plane fitted through the central pyrazole ring has an r.m.s. deviation of 0.0018 Å [0.0038 Å], showing it to be essentially planar. The benzene­sulfonamide ring is rotated by 46.79 (10)° [48.72 (7)°] from the plane of the pyrazole ring, while the bromo­benzene ring is essentially planar (r.m.s. deviation of a plane fitted through the one Br and all six C atoms = 0.0303 Å [0.0196 Å]) and is rotated by 44.85 (8)° [35.11 (9)°] from the plane of the pyrazole ring. The propanoic acid group has an extended planar structure (r.m.s. deviation of a mean plane fitted through atoms C16, C17, C18, O3 and O4 = 0.0581 Å [0.0403 Å]) and the group is rotated by 83.07 (10)° [24.85 (12)°] from the plane of the pyrazole ring. Fig. 4 shows an overlay of the two independent mol­ecules, formed by fitting the two pyrazole rings, and from this the differences in the relative orientations of the benzyl rings and the propanoic acid groups can be clearly seen.

An overlay of mol­ecules A (lighter shading) and B (black) in (II), formed by fitting the pyrazole rings, with an r.m.s. deviation of 0.0072 Å.

The crystal structure makes extensive use of hydrogen bonding (Table 2), forming a thick two-dimensional hydrogen-bonded structure. Fig. 5 shows a c-axis projection of part of the structure, showing how two different hydrogen-bonding motifs, one (11) and one (13), allow the structure to propagate along the b axis. The role of water is crucial here since it acts as both donor (two O—HO inter­actions) and acceptor (one N—HO inter­action), allowing both ring motifs to form. By contrast, the diethyl ether acts as a space-filling hydrogen-bond acceptor in a D inter­action with one sulfonamide donor site of mol­ecule B. Further D inter­actions, one N—HO with sulfonamide as both donor and acceptor and a second N—HO with sulfonamide as donor and an adjacent propanoic acid group as acceptor, allow the two-dimensional hydrogen-bonded sheet structure to grow. Several C—HO interactions are also found in (II). Atoms O3 and O51 are of note, both acting as bifurcated acceptors: O3 is an acceptor from C8 and C59, and O51 acts as a bifurcated acceptor from C15 and C51.

Part of the crystal structure of (II), projected along the c axis. The long a axis has been truncated. Mol­ecules are coloured according to symmetry equivalence as in Fig. 4. Dashed lines indicate hydrogen bonds. The dichloro­methane...

The third direction is dominated by BrBr inter­actions. The refined BrBr distance is 3.5787 (9) Å. This is consistent with data derived from the CSD; a search for nonbonded BrBr contacts between two Br atoms bonded to benzyl rings yielded 741 hits, with an average BrBr distance of 3.576 Å. The BrBr inter­actions, propagating along the [101] direction, link the hydrogen-bonded sheets together to form the overall crystal structure. Mol­ecules of dichloro­methane are also found between the sheets, although there are no significant inter­actions between dichloro­methane and adjacent mol­ecules.<!?tpb=11.3pt>

Experimental

The title compounds were synthesized by a two-step procedure. 6-(4-Bromo­phenyl)-4,6-dioxohexan­oic acid and 4,6-dioxo-6-p-tolyl­hex­an­oic acid were synthesized according to a modified literature method (Murray et al., 1991), using NaHMDS in place of LiHMDS; further details are available in the archived CIF.

For the preparation of (I), a mixture of 4,6-dioxo-6-p-tolyl­hexan­oic acid (1.639 g, 7 mmol), 4-sulfonamido­phenyl­hydrazine hydro­chloride (1.56 g, 7 mmol) and Et3N (0.97 ml, 7 mmol) were combined in MeOH (8 ml) and stirred at room temperature for 6 h. The mixture was then concentrated in vacuo to a residue which was partitioned between Et2O (40 ml) and 5% aqueous HCl (12.5 ml). The ether layer was separated, washed with 5% aqueous HCl (2 × 10 ml) and brine (10 ml), dried over Na2SO4, filtered, and concentrated to a residue. The crude residue was flash chromatographed on silica gel with a hexa­ne–EtOAc–AcOH (6:2:1) eluant, then recrystallized from methanol, yielding colourless crystals of (I). For C19H19N3O4S: calculated mass = 385.4 g mol−1 and observed mass (LQ-ESI MS) = 386.1 g mol−1.

For the preparation of (II), a mixture of 6-(4-bromo­phenyl)-4,6-dioxohexan­oic acid (299 mg, 1 mmol), 4-sulfonamido­phenyl­hy­dra­zine hydro­chloride (224 mg, 1 mmol) and Et3N (0.1 ml, 1 mmol) were combined in MeOH (8 ml) and stirred at room temperature for 6 h. The mixture was then concentrated in vacuo to a residue, which was partitioned between Et2O (40 ml) and 5% aqueous HCl (12.5 ml). The ether layer was separated, washed with 5% aqueous HCl (2 × 10 ml) and brine (10 ml), dried over Na2SO4, filtered, and concentrated to a residue. The crude residue was flash chromatographed on silica gel with a 1:1 eluant of hexane and EtOAc, and recrystallized from diethyl ether and dichloro­methane, yielding colourless crystals of (II). For C18H16BrN3O4S: yield 0.47 g; calculated mass = 450.31 g mol−1 and observed mass (LQ-ESI MS) = 452.0 g mol−1.

Refinement

R[F2 > 2σ(F2)] = 0.037

wR(F2) = 0.105

S = 1.02

8605 reflections

595 parameters

2 restraints

H atoms treated by a mixture of independent and constrained refinement

Δρmax = 0.84 e Å−3

Δρmin = −0.43 e Å−3

In (I), all atoms, including H atoms, were freely refined. In (II), O- and N-bound H atoms were refined with Uiso(H) = 1.2Ueq(O,N), but without distance restraints. Other H atoms were placed in geometrically optimized positions and refined using a riding model with Uiso(H) = 1.2Ueq(C) or 1.5Ueq(methyl C), and with fixed C—H distances of 0.95 Å for aryl, 0.98 Å for methyl and 0.99 Å for methyl­ene H atoms. The dichloro­methane atom site occupancies were freely refined to 0.722 (3).

Acknowledgments

This work was supported by grants from the United States Public Health Service and the National Institute on Drug Abuse. The diffractometer was purchased with funding from the NSF (grant No. CHE-9610347).

Footnotes

Supplementary data for this paper are available from the IUCr electronic archives (Reference: FN3023). Services for accessing these data are described at the back of the journal.